Fundamentals of pharmacology

Summary

The action of a drug depends on multiple factors. Pharmacokinetics concerns what the body does to the drug. Pharmacodynamics, on the other hand, concerns what the drug does to the body. Furthermore, when a drug is administered in combination with other drugs, a variety of drug interactions may take place that synergistically or antagonistically modify the effect of the given drug (e.g., the activation or inhibition of cytochrome p450 enzymes by certain medications). The knowledge of drug interactions and the pharmacokinetic properties of a drug help to determine the ideal route of administration (topical, oral, IV). Drugs that are eliminated by the liver may attain high serum concentrations when hepatic function is impaired, which increases the risk of drug toxicity. The same principle applies to drugs that are eliminated via the kidneys.

Biotransformationreactions take place in the liver; and affect both endogenous and exogenous substances. The main purpose of biotransformation is to detoxify a drug and alter its chemical structure to facilitate its elimination.

Types of drug kinetics

Zero order kinetics: : The rate of metabolism and/or elimination remains constant and is independent of the concentration of the drug (e.g., metabolism of alcohol)

First order kinetics: : The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (applies to most drugs)

Agonist: : a drug that has a similar effect to that of the endogenousreceptor activator (e.g., β2 agonists)

Antagonist: a drug that binds to a receptor and prevents its activation. Types of antagonism include:

Competitive antagonist:The agonist and the antagonist compete to bind to the same receptor; . Inhibits the effect of the agonist in a dose-dependent fashion → higher concentration of the agonist is needed to achieve same efficacy (e.g., there is a decrease in potency)

Reversible competitive antagonists

Irreversible competitive antagonists

Non-competitive antagonist: The drug binds at a site other than the agonist-binding site (also called allosteric site) and changes the structure of the agonist binding site and decreases the affinity of the agonist

Functional (physiological); antagonist: In this type of antagonism, two different molecules working through separate receptors produce physiologically opposite effects.

Potency (ED50): The potency of a drug is measured as the dose required to produce a pharmacological response of a specified intensity. Potency is a property that is dependent on both drug affinity and drug efficacy.

Pharmacogenetics

Pharmacogeneticsdeals with genetic variation in the expression of enzymes that metabolize drugs. These genetic differences can cause the observed drug response to deviate from the expected response and/or increase the risk of side effects:

If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:

A hyperactive variant of the enzyme decreases the drug response.

A hypoactive variant of the enzyme can cause cumulative drug effects and thus increase the risk of side effects.

The reverse is true if the enzyme is responsible for the activation of a drug.

The highest concentration of CYP enzymes is found within the centrilobular hepatocytes

CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it.

The effects of drugs that are activated by CYP enzymes are increased by enzyme induction and decreased by enzyme inhibition.

The effects of drugs that are broken down by CYP enzymes are decreased by enzyme induction and increased by enzyme inhibition.

Ultrarapid metabolizers: The activity of CYP2D6 is increased in individuals with a duplication on chromosome 22. Such individuals require a significantly higher dose for the desired effect to be achieved!